Objective: To investigate the protective effect of the specific tyrosine receptor kinase B (TrkB) agonist 7,8-dihydroxyflavone in spinal cord injury and the involved mechanisms. Methods: A total of 130 male ICR mice were randomly divided into five groups, including a sham-operated group, spinal cord injury group, spinal cord injury + solvent group, spinal cord injury + 7,8-dihydroxyflavone (3 mg/kg) group, and spinal cord injury + 7,8-dihydroxyflavone (5 mg/kg) group. The spinal cord injury model was established via the cross-clamp method (the spinal cord at the level of T7-T11 was exposed). 7,8-dihydroxyflavone or a solvent was injected intraperitoneally 30 minutes after the induction of injury. Protein expression of p-TrkB, p-Akt, caspase-3, and Bcl-2 was examined using immunoblotting 24 hours after the spinal cord injury was induced. HE staining and in situ TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling) assays were used to detect neuronal damage. Another batch of mice were maintained for 14 days after the spinal cord injury was induced, administered 7,8-dihydroxyflavone daily at the same time point, and assessed for neurological function. Results: 7,8-dihydroxyflavone significantly upregulated the protein expression of p-TrkB and p-Akt, suppressed the expression of the caspase-3 protein, increased Bcl-2 protein expression, and reduced neuronal apoptosis. Furthermore, 7,8-dihydroxyflavone remarkably improved the neurological function scores after the occurrence of spinal cord injury. Conclusions: A significant neuroprotective effect was induced by 7,8-dihydroxyflavone in mice with spinal cord injury, and 7,8-dihydroxyflavone may be used for the clinical treatment of patients with spinal cord injury.